ESPE Yearbook of Paediatric Endocrinology

Brief Summary: This phase 3, multinational, randomized clinical trial (CAHtalyst, NCT04806451) in pediatric patients with CAH, evaluated the efficacy of crinecerfont to improve androgen control and enable GC dose reduction to a physiological range.

Comment: Congenital adrenal hyperplasia (CAH) comprises several rare autosomal recessive conditions resulting in disordered adrenal steroidogenesis. Pathogenic variants in the CYP21A2 gene encoding steroid 21-hydroxylase, are responsible for ~95% of cases of CAH (1–4). Patients with classic CAH due to 21-hydroxylase deficiency have cortisol and often aldosterone deficiency from birth onwards (2). Glucocorticoids (GCs) are used for cortisol replacement therapy in patients with classical CAH. However, increased, supraphysiologic doses of GC are often needed to achieve adequate adrenal androgen reduction (1–4). Chronic supraphysiologic GC exposure results in multiple complications, such as decreased bone density, increased fracture risk, obesity, insulin resistance, diabetes mellitus, hyperlipidemia, hypertension, and psychological disturbances (1-6). One promising new strategy for reducing adrenal androgen overproduction through a GC-independent mechanism is corticotropin-releasing factor (CRF) type 1 receptor (CRF1) antagonism to reduce ACTH secretion, thus potentially allowing for physiological GC dosing (7). Crinecerfont is a novel oral CRF1 antagonist that reduced key hormone biomarkers in phase 2 studies in adults (NCT0352588627) and adolescents (NCT0404514528) with CAH.

This phase 3, multinational trial randomized (in 2:1 ratio) 103 children with classic CAH to receive crinecerfont or placebo for 28 weeks. A stable GC dose was maintained for 4 weeks, and the dose was then adjusted to a target of 8.0–10.0 mg/m²/day of hydrocortisone dose equivalent, provided that the androstenedione concentration was controlled (≤120% of the baseline concentration or within the reference range). Follow-up was high at 28 weeks (n=100, 97%). At baseline, mean GC dose was 16.4 mg/m²/day, and mean androstenedione concentration 431 ng/dL (15.0 nmol/L). At week 4, androstenedione was substantially reduced on crinecerfont (-197 ng/dL) but increased on placebo (+71 ng/dL) (P<0.001); the mean androstenedione concentration prior to the morning GC dose was 208 ng/dL on crinecerfont, vs. 545 ng/dL on placebo. At week 28, mean GC dose had decreased (while androstenedione control was maintained) by 18.0% on crinecerfont but increased by 5.6% on placebo (P<0.001).

These findings demonstrate the efficacy of crinecerfont to reduce elevated androstenedione concentrations in children with classical CAH. It also decreased GC doses from supraphysiologic to physiologic levels while maintaining androstenedione control.

References: 1. Speiser PW, Arlt W, Auchus RJ, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2018; 103: 4043–88. 2. Claahsen-van der Grinten HL, Speiser PW, Ahmed SF, et al. Congenital adrenal hyperplasia-current insights in pathophysiology, diagnostics, and management. Endocr Rev 2022; 43: 91–159. 3. Mallappa A, Merke DP. Management challenges and therapeutic advances in congenital adrenal hyperplasia. Nat Rev Endocrinol 2022; 18: 337–52. 4. Merke DP, Auchus RJ. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency. N Engl J Med 2020; 383: 1248–61. 5. Turcu AF, Auchus RJ. Adrenal steroidogenesis and congenital adrenal hyperplasia. Endocrinol Metab Clin North Am 2015; 44: 275–96. 6. Reisch N. Review of health problems in adult patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Exp Clin Endocrinol Diabetes 2019; 127: 171–7. 7. Prete A, Auchus RJ, Ross RJ. Clinical advances in the pharmacotherapy of congenital adrenal hyperplasia. Eur J Endocrinol 2021; 186: R1–R14.